Systemic lupus erythematosus (SLE) is an autoimmune disease that preferentially afflicts young women. Although considered a connective tissue disease, SLE harms a variety of organ systems, including the skin, joints, kidney and brain. Management of active SLE frequently requires the use of multiple non-specific immunosuppressive and cytotoxic drugs that are associated with toxicities and often have limited efficacy. Recently, we have made the surprising discovery that certain FDA-approved Human Immunodeficiency Virus (HIV) protease inhibitors show promise in a variety of preclinical lupus models. Among these, nelfinavir (brand name Viracept), possesses a relatively benign safety profile in HIV patients and is not likely to be immunosuppressive or cause adverse events in lupus patients. On the strength of both nelfinavir's known safety and our preclinical data demonstrating that nelfinavir acts, in part, as a decoy antigen to quench the pathogenic lupus anti-dsDNA autoantibodies, we propose to assess the safety and preliminary efficacy of nelfinavir as a lupus therapeutic in a pilot feasibility phase IIa clinical trial. We will pre-scren subjects for elevated anti-dsDNA autoantibody titers and incorporate early surrogate efficacy measures into this trial design. These and other innovations will bring a personalized medicine approach to lupus and contribute to the likelihood of the trial's success. Moreover, it has not escaped our notice that the repurposing of an FDA- approved drug into a new indication will facilitate an extremely rapid path into an urgent unmet medical need. The successful completion of this proof-of-concept study will lay the groundwork for a definitive clinical trial.